Project 1 Title: TGF, PI3K and HER2 pathways in breast cancer metastasis Leader: Joan Massagu, Ph.D. Key Personnel: Swarnali Acharyya, PhD, Research Associate Yilong Zou, Graduate Student PROJECT SUMMARY: Even if diagnosed at an early stage and surgically removed, breast cancer can relapse within months to decades in bones, lung, liver and brain, as well as locally. Although the five-year disease free survival rate is 89% in patients with well-treated localized breast cancer, the appearance of metastatic disease is almost always a harbinger of eventual cancer mortality. Under the auspices of this P01 grant, we uncovered important roles the TGF in in triple negative (TN) and HER2+ breast cancer, and unexpected roles of the PI3K pathway and CXCR2 signaling in breast cancer metastasis and chemoresistance. Progress includes (i) generation of mouse models of breast cancer metastasis, now used in labs worldwide; (ii) alteration of the TGF pathway from tumor suppressor to metastasis promoter; (iii) identification of breast cancer metastasis genes and pathways; and (iv) discovery of the tumor self-seeding process, which views tumor dissemination as a multidirectional process. Since the last competitive renewal our work has illuminated the intersection of the TGF and PI3K pathways in oncogenesis and metastasis, and heightened the interest on these mediators in the survival and chemoresistance in disseminated breast cancer cells. Our Specific Aim 1 is to identify mediators of TGF-driven metastasis. The identification of TGF target genes that mediate its pro- metastatic action would help target metastasis downstream of TGF and its receptors. We will use newly developed TRAP technology to identify TGF regulated genes in breast metastatic cancer cells in host tissues. In Specific Aim 2 we will define the metastasis suppressive capacity of PI3K-AKT and CXCR2 inhibitors. Our recent work identified the PI3K pathway as a critical mediator of micrometastatic cancer cell survival and a protector against reinstated TGF-dependent tumor suppression, and CXCR2 signaling as an important defense of breast cancer cells against chemotherapy. In collaboration with J. Baselga, S. Chandarlapaty, L. Norton and N. Rosen, we will investigate farmacologic strategies targeting these effectors to define their effectiveness against disseminated breast cancer. Our Specific Aim 3 is to identify metastasis genes and functions in HER2+ breast cancer. HER2+ breast cancer is presently in a crisis of increased incidence of brain metastasis, yet little is known about the molecular drivers. There is also extensive evidence that TGF enhances metastasis in this type of breast cancer. Based on new models of HER2+ breast cancer metastasis that we have recently developed, we will identify genes that drive metastasis, in particular metastasis to brain, in HER2+ breast cancer, and the impact of TGF in this process. With S. Lowe we will use innovative shRNA screening techniques to functionally characterize the candidate metastasis genes. Thus, the continuation of the present P01 is focused on studies that directly emerged from our recent progress and rely on collaborations with the other P01 participants for the progress against breast cancer metastasis.